Phthalimide, alkyl, reaction with

The negatively charged nitrogen atom of the salt of phthalimide is a good nucleophile. It displaces halides from primary alkyl halides and tosylate groups from primary tosylates to yield an N-alkylated phthalimide. This reaction, with its related workup procedures, is called the Gabriel synthesis. 

The reaction of potassium phthalimide 1 with an alkyl halide 2 leads to formation of a N-alkyl phthalimide 3/ which can be cleaved hydrolytically or by reaction with hydrazine (Ing-Manske variant) to yield a primary amine 5. This route owes its importance as a synthetic method to the fact that primary amines are prepared selectively, not contaminated with secondary or tertiary amines. 

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

Pi peridinobenzimidazole also serves as starting material for the antipsychotic agent halopemide (69). In the absence of a specific reference, one may speculate that the first step involves alkylation with bromochloro-ethane to give halide The chlorine may then be converted to the primary amine by any of several methods such as reaction with phthalimide anion followed by hydrazinolysis. Acylation with j -fluorobenzoyl chloride then gives the desired product. 

Gabriel amine synthesis (Section 24.6) A method for preparing an amine by SN2 reaction of an alkyl halide with potassium phthalimide. followed by hydrolysis. 

Yield.—Almost theoretical M.P. 118°. (B., 19,2991 0. S., XIII., 82.) Reaction CXXV. Action of Alkyl Halides on Phthalimide (Potassium Salt). —When an alcoholic solution of phthalimide is treated with the theoretical quantity of caustic potash dissolved in alcohol, a crystalline compound—potassium phthalimide—separates out (see p. 427). 

An alternative reagent equivalent for the amide anion synthon is the potassium salt of phthalimide which can only react with one molecular proportion of alkyl halide. The resulting JV-alkylphthalimide is then cleaved to the primary amine (the Gabriel synthesis). The preliminary preparation of potassium phthalimide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75% ethanol) may be avoided in some cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The cleavage of the JV-substituted phthalimide is best effected by reaction with hydrazine hydrate and then heating the reaction mixture with hydrochloric acid. The insoluble phthalylhydrazide is filtered off, leaving the amine hydrochloride in solution from which the amine may be liberated and isolated in the appropriate manner. 

Potassium phthalimide is a "NH2-synthon which allows the preparation of primary amines by reaction with alkyl halides. After alkylation, the phthalimid is not nucleophile and does not react anymore. Product is cleaved by reaction with base or hydrazine, which leads to a stable cyclic product. 

A new route to bromopyrroles was developed. It depends on addition of HBr to A-protected y-aminoynones. When applied to alkynyl ketones, 2-aryl or 2-alkyl 4-bromopyrroles are formed. 2-Alkyl or 2-aryl 3-bromopyrroles can be obtained from acetals of V-aminoynals. The ketones are made from A -protected propargylamines by ( -acylation. The acetals are made from 3,3-diethoxypropyne by addition to an aldehyde followed by introduction of the amino group by reaction with phthalimide under Mitsunobu conditions. <95S276>... 

Gramme is a common precursor for indol-3-ylmethylation of enolates and other nucleophiles. Such reactions normally occur by an elimination-addition mechanism. Following development of procedures for 4-substitution via directed lithiation with l-(tri-/w-propylsilyl)-gramine, Iwao and Motoi have developed conditions for tandem nucleophilic substitution of the dimethylamino group. Quatemization followed by reaction with a nucleophile in the presence of TBAF leads to alkylation. <95TL5929> The carbon nucleophiles which were successfully used include nitromethane, methyl acetoacetate, diethyl malonate and diethyl 2-(acetamido)malonate. Phthalimide, thiophenol, TMS-CN and TMS-Nj were also used as sources of nucleophiles. 

The overall reaction involves replacing the halogen atom of the alkyl halide with an NH, unit. Another method is the Gabriel synthesis of amines. This involves treating phthalimide with KOH to abstract the N-H proton. The N-H proton of phthalimide is more acidic (pK9) than the N-H proton of an amide since the anion formed can be stabilised by resonance with both neighbouring carbonyl groups. The phthalimide ion can then be alkylated by treating it with an alkyl halide in nucleophilic substitution. 

Tertiary alkyl halides lose hydrogen halide in their reaction with potassium phthalimide. However, the t-alkylphthalimides are readily prepared by heating the corresponding t-alkylureas and phthalic anhydride to 200° to 240°. ... 

Alkynyl ketones can be formed from addition of alkynyllithium or Grignard reagents to phthalimides and then the products converted into pyrazoles by reaction with hydrazines. For example, A -alkyl-substituted phthalimides 633 were easily transformed to mono-, di-, or trisubstituted pyrazoles 634 via a one-pot addition/decyclization/cyclocon-densation process (Equation 131) <2002J(P1)207>. A -Alkyl-substituted phthalimides 635 were easily converted into di-, tri-, and tetrasubstituted pyrazoles 636 via a one-pot addition-decyclization-cyclocondensation process (Equation 132) <2003H(60)2499>. 

Alkylthiophosphonium salts (90) prepared fn>m thiol (89) can also be utilized as an alkylating reagent for phthalimide. The reaction proceeds with inversion of configuration at the reaction site (Scheme 39). ... 

Potassium phthalimide 1 is an NH2 synthon which, after alkylation, is no longer nucleophilic and therefore does not react any Anther. The alkylated phthalimide is cleaved by reaction with base leading to the requisite amine 3 and phthalic acid 4 as a byproduct. 

HMR-3647 (telithromycin TLM) (91i), one of the 11,12-cyclic carbamate ketolides bearing various heterocyclic butyl substituents at 11-Ai of carbamate (91), was synthesized from 10,ll-anhydro-12-O-imidazolyl carbonyl ketolide (90) by the reaction with the corresponding amine (Scheme 8) [125]. The synthesis of the heterocyclicbutylamines (Scheme 8, a-i) was achieved by alkylation of the respective heterocyclic amine with 4-bromobutylphthalimide in the presence of NaH or K2CO3 in DMF, followed by hydrazinolysis of phthalimide intermediates. The overall yields of these steps were 24-64%. 

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